Increased expression of dihydrodiol dehydrogenase induces resistance to cisplatin in human ovarian carcinoma cells.

ABSTRACT

We employed cDNA microarrays to identify the differentially expressed genes in a cisplatin-sensitive parental (2008) human ovarian carcinoma cell line and its cisplatin-resistant variant (2008/C13*). Differential expression of five genes was found in the 2008/C13* cells, a result confirmed by semi-quantitative reverse transcription-PCR. The five genes were identified as fibroblast muscle-type tropomyosin and skeletal muscle-type tropomyosin, dihydrodiol dehydrogenase, apolipoprotein J and glucose-6-phosphate dehydrogenase variant-A. Treatment of the 2008 cells with cisplatin (at its IC(50) concentration of 2 microm) induced expression of these genes, as determined by semi-quantitative reverse transcription-PCR analysis using gene-specific primers. In contrast, treatment of the drug-resistant 2008/C13* cells with cisplatin (at its IC(50) concentration of 20 microm) did not lead to the induction of any of the aforementioned genes. Most importantly, constitutive overexpression of dihydrodiol dehydrogenase (but not the other genes) in the 2008 cells led to induction of cisplatin resistance, clearly indicating its role in the development of the resistance phenotype in the 2008/C13* cells. The development of cisplatin resistance in the transfected cells was associated with an increase in the dihydrodiol dehydrogenase enzyme activity. Although at present it is not clear how dihydrodiol dehydrogenase is involved in cisplatin resistance, the identification of this gene as a causal factor suggests the existence of a hitherto undefined pathway resulting in cisplatin resistance.